The present invention, in some embodiments thereof, relates to anti-HER3 antibodies and uses of same.
Growth factors and their transmembrane receptor tyrosine kinases regulate cellular proliferation and migration during both embryogenesis and oncogenesis. The HER family (1) includes four members, the epidermal growth factor receptor, EGFR (ErbB1/HER1), HER2 (c-Neu, ErbB2), HER3 (ErbB3) and HER4 (ErbB4). HER receptors harbor an extracellular domain consisting of four structural subdomains, referred to as domains I-IV (2), followed by a transmembrane domain and an intracellular domain, which provides tyrosine kinase activity. Kinase activation of the HER family members has generally been considered to involve ligand-induced active dimer formation. In this model, except in HER2, structural changes from a tethered to an untethered conformation exposing a dimerization arm (domain II) are induced following ligand induced activation. Therefore, HER proteins are able to form active homodimers or heterodimers or higher class oligomers (3-6). Additional studies revealed the existence of ligand-independent activated dimers, reported in case of receptor overexpression (7). Moreover, other studies reported inactive preformed free or half-free-ligand dimers presenting asymmetric arrangement of the intracellular kinase domain. These inactive dimers can subsequently be activated by ligand binding (8).
HER3, which presents a very low tyrosine kinase activity (9), has an influence on signaling pathways, via its preferential dimerization with EGFR or HER2 and its subsequent phosphorylation by these active tyrosine kinases. These receptors and their many ligands form a layered signaling network, which is multiply involved in human cancer (6). HER3 is activated upon neuregulin (NRG) binding, mainly NRG1β, but unlike EGFR, HER2 and HER4, HER3 does not form homodimers upon ligand binding (10). Similar to EGFR and HER2, the identification of somatic mutations in HER3 was recently reported in colon and in gastric cancer (11), reflecting the importance of this receptor for tumor progression.
Targeted therapies against HER family members using monoclonal antibodies (mAbs) are widely and commonly used in cancer therapy. For example, trastuzumab (Herceptin) that targets HER2 is currently employed routinely in breast cancer therapy (12, 13). However, due to the adaptive character of this disease, the majority of breast cancers become trastuzumab-resistant after prolonged treatment. Several studies reported that trastuzumab resistant tumors show strong expression of HER3 (14). Moreover, HER3 is also implicated in the development of resistance to treatment with other HER-targeted therapies (e.g., cetuximab or kinase inhibitors such as Lapatinib) (15, 16), IGFR-targeted therapies (17) or chemotherapeutic agents (18).
Anti-HER3 antibodies are already in development in several laboratories (19) and some of them are currently in phase I clinical trials. These are MM-121 (20) from Merrimack, U3-1287/AMG888 (21) from U3-Pharma/AMGEN, AV-203 (19) from Aveo and RO5479599 (22) from Roche. In addition, some bispecific molecules targeting HER3 and another receptor have been developed and three of them are currently in phase I clinical trials. These are MM-111 (23) (HER2/HER3; Merrimack), MEHD7945A (24, 25) (EGFR/HER3; Genentech) and MM-141 (26) (IGFR1/HER3; Merrimack). These bispecific strategies are based on the assumption that the dual targeting of two receptors from the EGFR family might be effective in terms of tumor inhibition.
Drugs targeting HER3 that are currently developed or in clinical trials show promising results, but their efficacy can be viewed as modest (32). It is therefore imperative to develop new strategies to improve the benefit of HER3 targeting.